Multi‐organ dysfunction secondary to abrupt discontinuation of voxelotor in a patient with severe sickle cell disease
Authors: Vishnu Nagalapuram, Julie Kanter
Journal: American Journal of Hematology (2022)

Sickle cell disease (SCD) is the most common inherited hematologic disorder in the United States (US).1 Until 2017, hydroxyurea (HU) was the only approved disease modifying therapy. Three new drugs have been approved in the recent years: l-glutamine, voxelotor, and crizanlizumab.2 Importantly, <200 individuals were treated with each medication at the approved dose prior to approval. Further, these clinical trials restricted the inclusion of people with SCD who had significant cardio renal disease. Thus, little is known about these potentially disease-modifying medications in severe SCD. One of these medications, voxelotor directly alters the red blood cell (RBC) by increasing the oxygen affinity of hemoglobin (Hb) through allosteric modification, thereby reducing the concentration of deoxygenated hemoglobin S (HbS), and preventing sickling.3 The phase II-III trial that led to the approval of voxelotor (HOPE trial), demonstrated that voxelotor increases Hb levels and reduces hemolysis in >60% of patients at the 1500 mg dose.4 The trial met the primary end point of a positive Hb response of >1 g/dl above baseline at week 24 but failed to meet any of the key secondary clinical endpoints that were initially required for drug approval. Common adverse events reported during the HOPE trial and the 72-week follow-up study included headache, diarrhea, and nausea.5 This is a 27-year-old Black woman with SCD (HbSS) complicated by frequent vaso-occlusive crisis (VOC), chronic kidney disease, pulmonary hypertension, chronic pain, systemic hypertension, and significant RBC allo-immunization with a history of delayed hemolytic transfusion reactions (DHTRs). Prior to starting voxelotor, she was on erythropoietin (EPO) 40 000 units (2–3 times/week) and HU 500 mg daily (low dose due to nausea). Her pre-voxelotor labs (baseline): Hb 7.5 g/dl, absolute reticulocyte count (ARC) 327/mm3, lactate dehydrogenase (LDH) 736 units/L, creatinine (Cr) 0.8 mg/dl, urine albumin-creatinine ratio 2760 mg/g, total bilirubin (T. bili) 1.3 mg/dl, brain natriuretic peptide (BNP) was 586 pg/ml, and Hb electrophoresis Hb S 92.9, Hb F 3.7, and Hb A2 3.4. Baseline vital signs (VS): oxygen saturation (SaO2) 97% on room air, blood pressure (BP) 133/93, and heart rate (HR) of 94. Her most recent trans-thoracic echocardiogram (TTE) showed left ventricular ejection fraction (LVEF) 55–60%, a tricuspid regurgitant jet velocity (TRJV) of 2.95 m/s and right ventricular systolic pressure (RVSP) elevated at 40–50 mm Hg. To reduce the frequency of EPO injections and potentially improve her pulmonary hypertension, she was started on voxelotor 1000 mg daily (dose chosen to optimize her pill burden) while continuing HU and EPO injections. EPO was stopped on day 13 when Hb was 9.9 g/dl, LDH 460 units/L, ARC 21/mm3, T. bili 1.2 mg/dl, and O2sat 98% on room air. On day 48, her Hb was 10.4 g/dl, T. bili 1.3 mg/dl, and CR 0.7 mg/dl. Initial event (day 59): She presented to the SCD day hospital with acute VOC. She reported missing voxelotor for 3 days. She was in moderate distress (VS HR 129 bpm, BP 192/113 mm Hg, and O2 Sat 83% on room air). Laboratories: Hb 5.9 g/dl, ARC 298/mm3, LDH 1014 units/L, Cr 1.3 mg/dl, T. Bili 1.4 mg/dl, and BNP 2777 pg/ml. Chest radiograph revealed mild pulmonary edema. She was admitted for management of acute heart failure, hypoxic respiratory failure, and pain control. The patient could not be transfused due to history of DHTR, so she was restarted on EPO 40 000 units daily in conjunction with voxelotor and treatment with intravenous iron. On day 65, her Hb began to increase but she remained hypoxic. Her TTE showed LVEF 40%, TRJV of 3.81 m/s, and RVSP of 73 mm Hg. Right heart catheterization revealed mean pulmonary artery pressure of 52 mm Hg with preserved cardiac index. She was not treated with vasopressor medications, hemodialysis, or transfusion but recovered with above noted interventions. At the time of discharge (day 74), her Hb was 9.2 g/dl, and her O2sat was >93% on room air. Following her discharge, she resumed EPO 40 000 units weekly until Hb >7 g/dl. The events leading to the previous hospitalization were discussed in detail including her abrupt discontinuation of voxelotor. She insisted she would remain diligent to the current regimen (HU 500 mg daily, voxelotor 1000 mg daily, and EPO weekly) and Table 1 shows consistent VS and labs for several weeks. She continued to require intermittent treatment for VOC (consistent with baseline). Second event: On day 112, she re-presented to the SCD day hospital with VOC after missing 4 days of voxelotor and HU. She was noted to be lethargic, unable to stay alert despite significant pain. She was in acute distress (HR 124, RR 24, and SaO2 of 60%) and was immediately started on oxygen (SaO2 improved to 93% on 5 L by face mask). Laboratories: Hb 5.4 g/dl, ARC 134 cells/mm3, LDH 2093 units/L, Cr 1.5 mg/dl, BNP 1166 pg/ml, and elevated troponin 354 ng/L (no ST-T wave changes on electrocardiogram). She was admitted to the intensive care unit where she remained abnormally somnolent despite complaining of diffuse pain and she was treated with high flow oxygen as well as EPO 40 000 units daily, voxelotor, and iron. A repeat TTE re-demonstrated similar of elevated TRJV of 3.74 m/s and RVSP of 71 mm Hg. She was continued on HU, voxelotor, and EPO, and discharged once she recovered (day 125). Following discharge, she returned to her “on medication” baseline. She asked to continue voxelotor and was instructed that a subsequent event would require us to stop the medication. She has not had any further episodes in the 7 months follow-up period. The limitations of a rare disease include the expedited approval of medications that are evaluated in small patient populations often representing the “healthiest” of patients. In the case of voxelotor, only 88 individuals had ever received the approved dose (1500 mg) at the time of approval. Furthermore, only 64 patients continued to receive the medication after the initial data cut-off date. Thus, while the medication was noted to be efficacious, only a very small number of people with SCD had received the approved dose for >24 weeks. Although the need for disease modifying therapies outweighs the risks of these expedited approvals, additional post-approval monitoring should be mandated. In the case of SCD, many adults are followed by primary care physicians or community oncologists instead of by SCD specialists due to the paucity of adult-focused specialists. However, new medications can be prescribed by any provider regardless of SCD-specific knowledge or training. This patient has severe, complicated SCD with few available treatment options. Voxelotor has not been systematically evaluated in patients with moderate–severe pulmonary hypertension or kidney disease. Thus, she was monitored weekly after initiation of voxelotor with laboratory and clinical assessments. Her response to therapy was positive and her visits were extended to monthly assessments. The abrupt (and accidental) discontinuation of therapy on two separate occasions led to acute worsening of anemia, increase in LDH, acute kidney injury, severe hypoxia, and heart failure. In both cases, the patient had taken a weekend vacation in which she had neglected to bring her medication with her as it was in a different location (pill box) than her other medications. There was no other cause of her acute decline outside of neglecting her voxelotor was identified and she was able to recover with resumption of medication (in conjunction with EPO and intravenous iron), further implicating its role in these acute events. While the timing of the events does not prove causality of the hyperhemolysis to the cessation of the medication (voxelotor), the repeated occurrences of these events enhance the potential for a causal (instead of coincidental) relationship. The pathophysiologic mechanism underlying these events is unclear. Because voxelotor increases the Hb oxygen affinity, there have been concerns voiced about poor tissue oxygen extraction leading to cellular hypoxia6; but without in vivo validation. This was not thought to be the cause of these events. However, as the medication can increase some individuals' baseline Hb by 25%–30%5 we hypothesize that the abrupt cessation of voxelotor results in more available Hb that may hemolyze. We hypothesize that patients with poor cardiopulmonary reserve cannot tolerate the brisk hemolysis concomitant with a significant change in oxygen carrying capacity, resulting in multi-organ dysfunction. We believe this problem was not seen during the trial as it likely occurs only in high-risk patients with cardio-renal disease that precluded their inclusion. Similarly, the authors believe this rebound response would not occur in those individuals without significant, baseline cardiopulmonary complications of their SCD. Notably, this patient does have improved hematological assessments with reduced hemolysis when stable on the medication and is able to maintain normal oxygen saturation on room air (though this is a measure of Hb oxygenation and not tissue oxygenation). However, it is unclear if the benefit is worth the additional risk for this individual patient. While other medications are known to have substantial complications from their abrupt discontinuation, many are studied in larger populations with more data available detailing the risks of stopping the medication as well as the treatment in those scenarios. In this case, of a rare disease population, this information is not yet available but deserves further study. We can draw several conclusions from these events. (1) Medications given expedited approval should be monitored more carefully due to the limited exposure during a clinical trial. (2) While it is not feasible to limit prescribing of medications such as voxelotor to only SCD specialists (given the paucity of available specialists), it is clear that more oversight is needed as well as additional education for prescribing physicians and patients on the potential risks and benefits of newly approved medications understanding the small population of individuals who have been previously exposed until sufficient post-approval evaluation can be completed. The paucity of adult SCD specialists is noted but prescribing physicians can partner with SCD specialists if needed. (3) Highest concern: Expensive medications such as voxelotor cannot be maintained hospital formularies. Hence, it is important for patients/families to bring their medication when admitted to the hospital to avoid abrupt discontinuation. Further, if their disease course worsens while being hospitalized, the patients may be diagnosed with a “severe vaso-occlusive crisis” without recognizing the potential impact of this medication's withdrawal. Thus, physicians treating individuals with SCD should be made aware of this potential complication. In addition, hospitals should have the means for providing the medication to prevent consequences of abrupt withdrawal. The authors declare no potential conflict of interest. Data available on request from the authors.